Process of preparing phosphorus esters



United States Patent "ice 3,518,261 PROCESS OF PREPARING PHOSPHORUSESTERS Thanh-Thuong Nguyen, Arcueil, and Daniel Demozay,

Villeurbanne, France, assignors to Pechiney-Progil-Societe pour leDeveloppement et la Vente de Specialites Chimiques, Paris, France NoDrawing. Filed June 15, 1966, Ser. No. 557,621 Claims priority,applicfiiorzFrance, June 18, 1965, 3 Int. Cl. C07d 87/46 US. Cl.260-2471 3 Claims ABSTRACT OF THE DISCLOSURE Trithioandtetrathio-phosphoric esters having the general formula RS Y l s-R RSprepared by the reaction of the halide of the R group with thetetramethyl ammonium salt of disubstituted derivatives oftrithio-phosphoric or tetrathio-phosphoric acids in the presence of asolvent.

This invention relates to new organic derivatives of phosphorus whichfind new and novel use and antiparasitics.

The invention also relates to a process for the preparation of variousnew trithioand tetrathio-phosphoric esters having the general formulaP-S-R in which R and R" represent alkyl radicals having from 1 to carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyland isopentyl, Y is oxygen or sulphur and R represents in which M is oneor more of the following groups including a halogen such as chlorine,bromine, iodine and fluorine, alkyl radicals such as methyl, ethyl,propyl, butyl, hexyl, octyl and the like, and such alkyl groupssubstituted by a halogen such as methyl chloride, ethylene dichloride,ethylene bromide and the like, nitro, cyano, alkoxy or thioalkyl groupsin which the alkyl component is of the type previously described orA-COOR in which A represents a methylene or ethylene radical, which maybe unsubstituted or substituted by alkyl, aryl, or carboxyalkyl groupssuch as methyl, ethyl, propyl, octyl, phenyl, tolyl, benzyl, naphthyland the like, R represents an alkyl radical containing from 1 to 5carbon atoms of the types previously described or in which R and R arethe same or different groups and in which R and/or R is hydrogen,saturated alkyl radicals containing from 1 to 5 carbon atoms of thetypes previously described or phenyl radicals and in which the alkyl andphenyl radicals may be unsubstituted or substituted by a halogen such aschlorine, bromine, fluo- 3,518,261 Patented June 30, 1970 rine andiodine, and in which, in addition, R and R may form with the nitrogenatom a heterocyclic radical which may contain another hetero atom suchas oxygen, or

where R and R are as defined above, and n is 1 or 2; in this case, thecompounds are preferably prepared in the form of a salt by reacting anacid or an alkyl halide with the basic form of the compound inaccordance with Examples 18 to 29 hereinafter set forth, or

where R, and R represent alkyl radicals containing from 1 to 5 carbonatoms as previously described while n is l or 2, or

(S) O 0R4 where R; and R represent alkyl radicals containing 1 to 5carbon atoms as previously described, It is 1 or 2 and Z is oxygen,sulphur or NH.

It will be appreciated that the group R is generally an alkyl radicalwhich may be substituted in various ways.

The invention relates to esters of the type described as new industrialproducts, to the process for their preparation and to their use asanti-parasitic agents and, in particular, as insecticides, pesticidesand fungicides.

The process for preparing the phosphoric esters embodying the featuresof this invention comprises reacting a halide of the group R with thetetramethylammonium salt of disubstituted derivatives oftrithiophosphoric acid and tetrathiophosphoric acids suitable forobtaining the required phosphorus derivative.

The tetramethylammonium salt is obtained by heating athiomethyldithioalkyl phosphate or thiophosphate with trimethylamine.The reaction is preferably carried out in the presence of a solvent byheating the phosphate or thiophosphate with an excess of trimethylaminefor a few hours at a temperature within the range of 70 to C. Thetetramethylammonium salt precipitates as it is formed. The course of thereaction is as follows:

The second stage of preparation comprises heating a substantiallyequimolar mixture of the halide X-R and the tetramethylammonium salt fora few hours to a temperature within the range of 50 and 100 C. in thepresence of solvent. The tetramethylammonium halide precipitates whilethe required phosphoric ester remains in solution.

The general course of the reaction is as follows:

In these formulae, R, R, Y and R are as defined above. X represents ahalogen atom such as chlorine or bromine. The following table shows byway of illustration, but not by way of limitation, examples of a numberof thio- 3 phosphorus products prepared by the method heretoforedescribed:

4 allowed to cool, after which 50 ml. of dry ethylether are added toprecipitate the formed tetramethylammonium salt. The product is thenfiltered to isolate the salt which R R Y R is washed with ether anddried in vacuo over phosphoric anhydride. 42 g. oftetramethylammonium-S,S-dimethyl- O CH2 OCH3 5 trithiophosphate meltingat 132 C. are obtained corresponding to a yield of 85%. on. on. o onr-\CN Tetramethylammonium S,S dimethyl trithiophosphate is a white, wellcrystallized and hygroscopic solid 01 F which is highly soluble inwater, alcohol, soluble in chlo- CHB C2115 0 Cl roform, acetonitrile,dimethylformamide and acetone, but

insoluble in ether and benzene. 01 F EXAMPLE 2 cans CZHS O E 02mTetramethylammonium-S,S-dimethyl-tetrathiophosphate 5S)71|T a -1 s O Q Amixture of 40.8 g. of cn snps and 100 ml. of a 28% by weight solution oftrimethylamine in acetone is on on s cH2-c1 heated for 12 hours at 95 C.in a hermetically sealed reaction flask. Further preparation is then asin Exam- 0 ple 1. 43.5 g. (corresponding to a yield of 82.5%) of tet-CHa (ma 0 CH COOC2H5 ramethylammonium S,S dimethyl tetrathiophosphate(M.P.=17l C.) are obtained. After recrystallization from anhydrousethanol, the product melts at 173 C. 2 5 2 5 s 0 02mTetrarnethylammonium S,S dimethyl tetrathiophos- E phate is a white,well crystallized and hygroscopic solid CH which is highly soluble inwater, soluble in alcohol and 3 30 chloroform but insoluble in ether andbenzene. CH3 CH3 S -CH2-CON 3 (CHaS)2PS-CH(COOC2H5)2 cm. 0111. sCHz-CHrCO-NH-Q l C2115 @2115 S 24.7 -g. (0.1 mol) of tetramethylammoniumS,S-dimethyl-trithiophosphate are dissolved in 100 ml. of chlo- (3H3roform. 23.9 g. (0.1 mol) of Br-CH(C0OC H are C H added to the resultingsolution. The reaction vessel is then hermetically sealed and heated-for 2 hours at 80 C. on

011 OH S -CH2 CON a ater bath- 0113 The flask is left to cool, and thetetramethylammonium bromide, quantitatively formed, is filtered olf. Thefil- The following examples y by way of mustra' trate is washed with asolution of n/ 10 sodium bicartion but not by way hmltanon the prqcessby 4D bonate to a slightly alkaline pH, and then washed with which anumber of or tetrathlophos'phonc esters water until neutral. Thechloroformic solution is then are Prepared dried over sodium sulphate.The product is filtered, the The first two examples illustrate thepreparation of the chloroform removed in vacuo and the product Purifiedtetramethylammonium salts used as starting material for by distillationin a nitrogen atmosphere the preparation of the esters to which Examples2 to 44 26 g. of product are obtained having a relate 150 C. at 0.01 mm.of mercury. Its refractive index at EXAMPLE 1 20 C. in relation to theline D of sodium is n =1.5415.Tetramethylammonium-S,S-dimethyl-trithiophosphate The compound is acolorless liquid which is soluble (CH2S)zP s/N(CH3)4 in organic solventsbut insoluble in water. The yield comll prises 81% of the theoretical.37.6 g. (0.2 mol) of (CH S) PO (B.P. at 1.1 mm. EXAMPLES4TO6 Hg=105) and100 ml. of a 28% by weight solution of The compounds set out in Table Iwere prepared as in trimethylamine in acetone, i.e. approximately 0.37mol, Example 3 by reacting tetramethylammonium S,S diare introduced intoa pressure-resistant reaction flask methyl-trithiophosphate and theassociated halogenated made of thick glass. derivative BrCH COOC H (4),BrCHCOOC H (5) After the flash has been hermetically sealed, it isheated and BrCH CH COOC H (6) in chloroformic mefor 8 hours at C. on awater bath. The flask is then dium.

TABLE I Example B.P., C./ Yield, No. Formula mm. Hg nmo percent 4mmmnrs-om-cooomt 112-510. 01 1.5705 61 5 (CH S)2l1l-SCHCOOC2H5 116/0.01 1. 5564 72 6 (CHaShfi-S-CHz-CHz-O O O C2115 EXAMPLE 7dimethyltetrathiophosphate under the conditions of Example 7 and yieldsa viscous, colorless residue Which crystallizes in a mixture of carbontetrachloride and petroleum ether. After recrystallization frompetroleum ether, the product, secured in a yield of 80%, melts at 38-39C.

EXAMPLE 11 A mixture of 24.7 g. (0.1 mol) oftetramethylammonium-S,S-dimethyl-trithiophosphate, 23.75 g.(0.1 mol) C1of ClCH CO-NH-C H Cl (2.4) and 75 ml. of chloroform, is heated for 5hours at 90. Tetramethylammonium fi' chloride begins to precipitateafter heating for 15 min- 0 T2] utes.

The reaction mixture is left to cool, and is then filtered 15 toeliminate the tetramethylammonium hydrochloride. 1L5 g'(0 05 mol) of 2,4 s trichlorobenzyl Chloride The filtrate is wash?d.with a splution ofsodillm bicar' are reacted for 4 hours at 80 with 13 g. (0.0525 mols)bonate until 1ts pH 1s ust alkaline, and then with water. oftetramethylammom-um s,S dimethyltrithiophoSphate The washing liquor 1sextracted w1th chloroform. :[he dissolved in mL of chloroform ThePreparation is chloroformic solutions are recombined, dried over sodiumthen completed, as in Example 7 16 g. of a Solid residue Sulphate,filtered the Solvent removed uflder vacumon are obtained which melts at62 C. after recrystallization and then at of merfmry for mmutes 31,50from petroleum ether. The yield corresponds to 70%.

30 g. of a crystalllzable viscous resldue are obtained. The yieldcomprises 80%. EXAMPLES 2 TO 17 After recrystallization fromcyclohexane, the product The procedure is the Same as that of Example 11melts at 90 C. cept that the compound tetramethylammonium-S,S-di-EXAMPLES 8 AND 9 methyltetrathiophosphate is substituted for thecompounds tetramethylammomum S,S dlmethyltrithiophosphate, in TheProcedure 18 the same as that of Example 7 Example 12, and the2,4,5-trichlorobenzyl chloride is cept that the compound ClCH -CO-NH-C HCl 1s sub- Substituted by stituted by the compound 01 C1-CH2-C-NH-CH3 Hmom- -01 1n Example 8 and in Example 13;

c1 o1-omo-N- o orcm-O-m in Example 14; in Example 9, to produce thecompounds as set forth in Table II. elem-4102 in Example 15;

TABLE 11 Yield, Example No. Formula M.P., C. percent a. (OHShfi-S-Cliz-fi-NH-CHAI) s0 61 9- (CH3S)2PS-CH2CN o 80 ll l LJ 1Colorless oil.

EXAMPLE 1O 7O ClCH CH -P(OCH in Example 16 and ClCH2 2 3)2 The foregoingcompound is produced by the reaction of N-methylchloroacetamide withtetramethylammoniurnin Example 17.

7 8 The compounds that are prepared are shown in the following TableIII:

TABLE I11 Yield, Formula. 131. in C/nun. Hg or M.P. percent: ExampleNo.-

12.- tcnasn -s-olr -c1 l\l.P.=55 70 ll 13 (OHzShP-S-GH C1 7s 01 l 14 H2s21 -sGH2-01 B.P.=179/0.05 slight decomp.-.

1s tonss)i i =s-cmNor so 10 (CI'I3S)g]I.[-S-CI'IzCH2-fi(001192B.P.=177/0.02 52.5

17 (CHaS)2]l['S-CH2CH2O-fi(0CH3)2 84 EXAMPLE 18 EXAMPLE 22(CHaS)2PSCHzCH2-N( 2H5)2 ll I 0 A mixture of 24.7 g. (0.1 mol) oftetramethylammomium-S,S-dimethyltrithiophosphate, 14.8 g. (0.11 mol) of0rns 2Ps-omoH2-N ammooon freshly prepared ClCH CH- N(C H5)2 and 50 ofchlO- ti 1'1 roform, is stirred for 6 hours at room temperature. Thetetramethylammonium chloride is eliminated by filtra tion. Thechloroform is removed in a vacuum formed by water jet and then at 0.01mm. of mercury for 30 minutes at The residue is taken up in 100 ml. ofanhydrous ether in order to precipitate all the tetramethylammonium saltsoluble in the chloroformic solution. The product is filtered and theether removed in vacuo. 23 g. of a colorless residue are obtained of theproduct, corresponding to a yield of 84.2%

EXAMPLES 19 to 21 The procedure of Example 18 was followed except thatthe tetramethylammonium S,S-dimethyltrithiophosphate is replaced by thecorresponding tetramethylammonium- S,S-dimethyltetrathiophosphate inExample 19 and the CICH CH N (C H 2 is replaced with 21 (CH3S)2PSCH2CH2NEXAMPLES 23 to 25 The procedure is the same as that of Example 22 exceptthat the corresponding tetrathiophosphate is substituted for thetrithiophosphate in Example 23 and in which in the trithiophosphate theIIT- C 2H5) 2 H group is substituted by a group in Example 24 and a 9 10group in Example 25. The following are the compounds produced:

' Yield, Example No: Formula M.P. percent 000 23(CHsShfiSClfiCHzlfKlzHsh/L' 118 87 H OOH 000- 24. (CH ShESCHzCHQlq o/tJ168 90 OOH 000- 25 (CHSSHIESCHZCHQFO 164 91 o H 000E EXAMPLE 26 phatewith the following substituted derivatives of benzyl 11.5 g. of 8,8dimethyl-S-(Z-diethylaminoethyl)-trithiophosphate in 10 ml. of acetoneare treated with 25 ml. rnlfof a 40% by weight solution of methylbromide in Example 30; acetone. The salt begins to precipitate after afew minutes at room temperature. The reaction mixture is left standingfor3 days at room temperature, after which the product Chen? is isolatedby filtration, washed with acetone, dried in vacuo over P 12.7 g. of aproduct are obtained which melts at 112 m Example 31; afterrecrystallization from a mixture of of iso- C 'H OH and 85% of acetone.The yield corresponds to F r EXAMPLES 27 to 29 The procedure is the sameas in Example 26 except that the corresponding tetrathiophosphate issubstituted for the trithiophosphate in Example 27, and in thetrithiophosphate of Example 26, the group o1-oH1 is substituted by thegroup 40 01 N( ,oBrl in Example 33;

C1-CH2 in Example 32;

in Example 29. The following are the compounds proin Example 28 andduced: in Example 34;

Yield Example No: Formula I M.P. percent 27 (CHaShfiSCHzCHzlTKCzHQz B!113 85 1 28 (CH S)2PSCH2CH2N 0 Br- 122-5 88 ll 1 O C 3 29 (CHShESCHgCHQlII B1" 144-7 84 Other salts may be prepared by a. similarprocess, particularly the halides, alkylhalides (containing 1 to 5carbon atoms) and the salts of aliphatic, saturated or unsaturatedmonoor di-acids containing 2 to carbon atoms. in Example EXAMPLES 30 TO36 Following the procedure of Example 11, the following compounds areprepared by reacting equimolar quantities oftetramethylamrnonium-S,S-dimethyltrithiophosin Example 36;

B.P OJmm. Hg Example Formula M.P Yield Remarks a0 cms =fi-s-cm-Br 170/5.64

31 wmsng-s-om-Q-m a2 (CH S)=fi-SOHPF 33 oms)l( lis-cml Recrystallizablefrom cyclohexane.

EXAMPLES 37 TO 39 The following compounds are obtained by a proceduresimilar to Examples 30 to 36 in whichtetramethylammonium-S,S-dimethyltetrathiophosphate is substituted forthe tetramethylammonium S,S dimethyltrithiophosphate in 7 Examples 30and 34 and in which Cl-OHz-QNO:

is also substituted for the compound in Example 30.

40 clorrOm ems) 11 -S-CH2 (CHaShlJ-S-CHzQ-NO:

1 Colorless oil, non-dlstlllable. 2 Non-distillable yellow oil.

EXAMlLES 4o, 41 AND 42 The followingcompounds were prepared by reacting(011110 -NH-cm-orrzc1 in Example 4 '(C3H'10) -PNH-CH CH -Cl in Example41, and (OH O) --P-'-CH CH Cl in Ex-- ample 42. withtetramethylammonium-S,S-dimethyltrithiophosphate or withtetramethylammonium-S,S-dimethyltetrathiophosphate under the conditionscomparable to those of Example 18.

Example Formula Yield Remarks 40 031-11 (iso) 66 (CH3S)21|l-S-(CH2)2NHP\O O OCaH1 (iso) 41 o Cal-I1 (iso) s (OHaS)2PS(CHz)2-NIIP O Cal-Ir (iso)(CHaS)z|I|S(CH2)2P S 0 CH3 1 Non-distillable, colorless oil.

Th d EXAMPLE 43 EXAMPLES OF THE ANTI-PARASITIC ACTIVITY e compoun OF THECOMPOUNDS ACCORDING TO THE IN- C O-O VENTION (3191120 CTN l Thefollowing examples show the results of tests con- CH2 HCH3 ducted todetermine the biological activity of the thiowas reacted withtetramethylammonium-S,S-dimethyltrithiophosphate under conditionssimilar to those of Example 7. The following compound is obtained in ayield of 75%;

EXAMPLE 44 The following disymmetrical compound was prepared:

(a) S,S-dimethyl-S-isopropyl-trithiophosphate was prepared by condensingtetramethylammonium-S,S-dimethyltrithiophosphate with isopropyl bromidein an acetone medium for 11 hours at 80. The resulting product whichcorresponds to the formula CH3S O CHaS is a liquid which boils at102.5/0.1 mm. of mercury.

(b) The tetramethylammonium salt of this asymmetrical phosphate was thenprepared by reacting it for 23 hours at 80 with trimethylamine. A solidcorresponding to the following formula was obtained:

CHaS O CsHyS (c) The compounds (basic form) was then prepared inaccordance with the procedure of Example 18. The reaction which takesplace in acetonitrile lasts for 4 hours at 80. The yield corresponds to66%.

(d) The oxalate of the product obtained according to (c) was prepared'by the process described in Example 22. The product which isprecipitated by the addition of methylethylketone is a solid which meltsat 103 C. The yield comprises 83%.

In the foregoing examples the formulation set forth at the toprepresents the identification of the compound prepared and which ispresent in the resulting product.

phosporus derivatives of this invention:

(I) Insecticidal tests (a) Tests on calandrae.-0.5 cc. of an acetonesolution containing 10 g./l. of active material are introduced onto thebottom of a Petri dish. After the acetone has been allowed to evaporate,100 weevils are placed in the dish. At the end of 10 days, the number ofliving and dead weevils is counted.

Under these conditions, the products of Examples 3, 4, 5, 6, 11, 12, 13,15, 21, 24, 30, 31, 32, 33, 34, 35, 37, 38, 41, 42 produce a 100%mortality rate.

(b) Tests on flies.-Flies are placed in a Petri dish with a gauze cover.5 cc. of a 2 g./l. of active material in acetone are sprayed onto thedish. At the end of 2 hours, the number of living and dead flies iscounted.

Under these conditions, the products of Examples 4, 5, 11, 25 and 42produce a mortality rate of 100%, while the product of Example 6produces a mortality rate of (c) Tests on calerpillars.-Flourimpregnated with 0.05% by weight of active material is introduced into atest tube. Some eggs of the Ephestia are placed on the flour and, at theend of 15 days, the tubes are examined to determine in which of them theeggs have hatched into larvae.

Under these conditions, the products of Examples 4, 5, 10, 11, 15, 23,25, 30, 31, 32, 33, 34, 35, 36, 38 and 42 kill off all the youngcaterpillars.

(II) Pesticidal tests Rings are cut from haricot leaves carrying apopulation of Tezranychus urticae, and are then treated by spraying witha solution containing 0.1 g./l. of active material. After 48 hours, thenumber of living and dead Acaridae is counted.

Under these conditions, the products of Examples 3, 4, 5, 9, 10, ll, 12,15, 17, 18, 21, 25, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 41 and 42produce a 100% Acaridae mortality rate. The products of Examples 11, 12,21, 30, 33 and 38 kill between 70% and of the Acaridae in a dosagecontaining the above concentration.

(III) Fungicidal tests An aqueous spray prepared from a wettable powdercontaining 20% of active material diluted to the required concentrationwas used for the following applications.

Inhibition, Product of percent Example N0.

Inhibition,

Product of Example No. percent 23 Untreated sample Inhibition, Productof Inhibition,

Product of Example N0. percent Example N 0. percent '(c) Certaincompounds such as, for example, those of Example 15, also show, onparasitic wood fungi (Coriolus versi-color, Chaetomium globosum andConl'ophora cerebella), an activity equivalent to that ofpentachlorophenol which is the conventional product employed to controlthese species of parasite.

The preceding examples illustrate the remarkable versatility of thecompounds of this invention. -In addition, their toxicity, in respect ofwarm-blooded animals, is in general low. When administeredintraperitoneally to mice in mg./kg., the DL is rarely less than 100and, more often, of the order of several hundreds. Finally, thesecompounds show a complete absence of phytotoxicity on plants. Thecombination of properties renders the compounds of this inventionparticularly suitable for use in controlling parasites affecting cropsand buildings.

For their application in parasite control, the products are generallyused in the form of compositions which, in addition to the activematerial, contain a generally inert diluent vehicle and, if desired, oneor more additives.

For example, the compositions according to the invention can be used inthe form of powders for dusting, wettable powders, emulsifiableconcentrates, aqueous dispersions, solutions, etc.

In the case of powders, as examples of the inert vehicle use can be madeof pyrophyllite, diatomite, talcum, clays, etc. In order to obtain awettable powder, a surface-active agent of any anionic, cationic ornon-ionic type is added,

such as represented by the following formulae of anion compounds:

or cationic compounds:

or nonionic compounds:

A1 0 R ILIZCHPHJ -2.

wherein R represents a lipophile group such as long chain alkylpolycyclic, aryl alkyl and derivatives thereof, M' represents a positiveion such as Na+ K+ NHp, X represents a negative ion such as Cl- Br- I"or other monovalent ion or /2 of a bivalent ion and A, A A represents H,alkyl, aryl or heterocyclic groups or residues.

In addition, it can be of advantage to add wetting agents, dispersantsor adhesives of the kind normally encountered in this type ofapplication, to the composition, depending upon the type of treatment tobe carried out and, in particular, upon the nature of the plants capableof being treated.

It will be understood that changes may be made in the details offormulation and preparation without departing from the spirit of theinvention, especially as defined in the following claims.

We claim:

1. A process for preparing trithioand tetrathiophosphoric esterscomprising reacting a compound of the formula R-X wherein R is amonovalent organic radical and X is a halogen, with thetetramethylammonium salt of disubstituted derivatives oftrithio-phosphoric acid or tetrathiophosphoric acid in substantiallyequimolecular proportions in the presence of a solvent.

2. The process as claimed in claim 1 in which the reaction is carriedout at a temperature within the range of 50-100 C.

3. The process as claimed in claim 1 in which the reaction is carriedout for a few hours.

References Cited FOREIGN PATENTS 2/1964 France.

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner U.S. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,518,261

Thanh-Thuong Nguyen et a1.

June 30, 1970 It is certified that error appears in the above identifiedpatent and that said Letters Patent are hereby corrected as shown below:

line 65, cancel the formula. Column 6, line 10,

Column 1, cancel the chlorine on the C6 position of the benzenemolecule;

line 27, "compounds" should read compound Column 7, Example 14, "(CH S)should read (CH S) Signed and sealed this 16th day of February 1971.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Edward M. Fletcher, Jr.

Col nmissioner of Patents Attesting Officer

